CN106389324B - A kind of process for producing reducing formula mannitol injection liquid crystallization - Google Patents
A kind of process for producing reducing formula mannitol injection liquid crystallization Download PDFInfo
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- CN106389324B CN106389324B CN201610979198.1A CN201610979198A CN106389324B CN 106389324 B CN106389324 B CN 106389324B CN 201610979198 A CN201610979198 A CN 201610979198A CN 106389324 B CN106389324 B CN 106389324B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The present invention relates to a kind of process for producing for reducing formula mannitol injection liquid crystallization, which is characterized in that operation under the B grade environmental condition that stock operation is under C grades of background, raw material cross ± 4.1 μm of 200 mesh i.e. 75 μm sieve；Filtering uses 0.1 μm of super filter core end-filtration；The preparation method and method of adjustment of pH adjusting agent: first measuring 180ml concentrated hydrochloric acid, inject water to 1000ml, shake up, and filters through 0.1 μm of filter membrane up to 2mol/L salt acid regulator；PH adjustment method: measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, under stiring in linear addition dilute preparing tank, stirs evenly；The use temperature of water for injection is determined as 90 DEG C -100 DEG C；Fine purifiation number is 10 flushings, and each washing pressure is not less than 0.15Mpa.Present invention reduces the mannitol crystallization ratios of the appearance in selling period, provide good product for clinical application.
Description
Technical field
The invention belongs to injection practical technique fields, and in particular to a kind of production system for reducing formula mannitol injection liquid crystallization
Standby technique.
Background technique
Formula mannitol injection liquid is clinically widely used in brain edema caused by treating a variety of causes, reduces intracranial pressure, intraocularly
Pressure prevents hernia cerebri, treats oedema, osmotic diuresis caused by large-area burns etc..Company passes through the condition of production over the years
And the analysis of market user's feedback information, the ratio of this product crystallization during storage cause potentially product quality 5% or so
Risk, it is difficult to guarantee that the quality of formula mannitol injection liquid is stablized in optimum state, therefore, establish by improving production technology preparation side
Method reduces product crystallization ratio, seems particularly necessary to the optimization and upgrading for guaranteeing the product.
However, it is 1:5.5 that the solubility of mannitol in water, which is (25 DEG C of room temperature), i.e., about 15% is saturated solution, because
This formula mannitol injection liquid (20%) is supersaturated solution, is easy that crystallization is precipitated, this is a common problem.It is exactly from production
On line, on the same day with a batch of sweet dew raw polyol make respectively come formula mannitol injection liquid crystallization bottle count up to it is complete different
It causes, some batch products have crystallization to be precipitated.Some batch nodeless mesh are precipitated, and some batches, which are precipitated, crystallizes more, some batch precipitations
Crystallization is few, and there is no very good solution methods at present.
It designs although having in the prior art from its component to reduce or solve the problems, such as crystallization, such as CN96120548.2 " nothing
Crystal mannitol injection and preparation method thereof ", which is related to a kind of non-crystal mannitol injection, which contains mannitol
100-200 grams, 10-100 grams of sodium chloride, water for injection adds to 1000 milliliters.Applicant thinks non-crystal mannitol injection obtained
Liquid nodeless mesh phenomenon at normal temperature, and do not change its curative effect.Clinical use is convenient, when can avoid delay rescue for urgent patient
Machine.But it is only unsatisfactory for experiment effect.
A kind of for another example CN201610481738.3 " formula mannitol injection liquid ", it is main active using 0.5%W/V needle is added
Charcoal, heating are boiled, and supernatant carries out ultrafiltration using the film that aperture is 20nm, and formula mannitol injection liquid crystallization probability is low, are had preferable
Stability, room temperature, low temperature are placed also do not crystallize for a long time, and through testing, visual inspection is observed 6 weeks at 0 DEG C, do not gone out
It now crystallizes, performance is stablized.
Therefore, inventors believe that, by formula mannitol injection liquid crystallize reason research, in production technology process for preparation
In take some aggregate measures, make formula mannitol injection liquid reduce crystalline polamer occur being only key.
Summary of the invention
In view of the above-mentioned problems, the purpose of the present invention is to provide kind of a process for producing for reduction formula mannitol injection liquid crystallization
Method.
Technical solution of the present invention:
A kind of process for producing reducing formula mannitol injection liquid crystallization, supplementary material packaging material quality requirement are pharmaceutical grade and note
Grade is penetrated, water for injection, purified water, bottle washout, bottle fine purifiation, preparation process, great circulation system, filling clean work area domain are passed through
Technical combinations reduce formula mannitol injection liquid crystallization, including stock；Concentrated compounding preparation；It is dilute to match preparation；Wash bottle；Wash plug；It is filling；It rolls
Lid；Sterilizing；Lamp inspection；Packaging: operation under the B grade environmental condition that stock operation is under C grades of background, raw material cross 200 mesh i.e. 75 μm
± 4.1 μm of sieves；Filtering uses 0.1 μm of super filter core end-filtration；The preparation method and method of adjustment of pH adjusting agent: it first measures
180ml concentrated hydrochloric acid, injects water to 1000ml, shakes up, and filters through 0.1 μm of filter membrane up to 2mol/L salt acid regulator；PH value
Method of adjustment: measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, under stiring in linear addition dilute preparing tank, stirring
Uniformly；The use temperature of water for injection is determined as 90 DEG C -100 DEG C；Fine purifiation number is 10 flushings, and each washing pressure is not less than
0.15Mpa。
Further,
(1) stock up: mannitol crosses 200 mesh in procedure for preparation: 75 μm of ± 4.1 μm of sieves become readily soluble after sieving
The superfine powder of solution；
(2) prepared by concentrated compounding:
A, dense preparing tank water for injection valve is opened, the water for injection through 0.1 μm of super filter element filtering, water are injected into tank
Temperature is not less than 90 DEG C, closes water for injection valve；Into tank, investment forms the medical charcoal of stud surface filtering layer, opens stirring,
Start spray pump, recycle 25 minutes, medical charcoal is made uniformly to be gathered in stud outer surface, opens blowdown valve, discharge；With same side
Method, dilute with forming filtering layer on the stud filter used；
B, the feeding cover for opening two dense preparing tanks respectively, be added into dense preparing tank 90 DEG C or more through 0.1 μm of super polyethers
The water for injection of sulfone filter element filtering opens stirring, opens steam blowdown valve and steam valve, is heated to boiling；Amount of preparation will be weighed up
Mannitol is divided into two parts, slowly after dissolution completely, is separately added into active carbon in two dense preparing tanks of investment respectively, with 90 DEG C with
On water for injection rinse top tank structure well, noresidue covers feeding cover, continues to stir；
C, it boils 40 minutes, bulk pharmaceutical chemicals is allowed sufficiently to dissolve, steam off valve and steam blowdown valve stop stirring, concentrated compounding terminates；
Concentrated wiring liquid is spare；
D, spray pump is opened, the mannitol concentrated solution by the good temperature of two tank concentrated compoundings not less than 85 DEG C is while hot through stud respectively
Filtering is sent into dilute preparing tank, after dense preparing tank medical fluid has been sent, successively with 90 DEG C or more through 0.1 μm of super polyether sulfone filter element filtering
Water for injection rinse concentrated compounding top tank structure to noresidue, open spray pump, water sent to dilute preparing tank, continues to put into dense preparing tank
90 DEG C or more of the water for injection through 0.1 μm of super polyether sulfone filter element filtering, the amount of being put into are the 1/3 of dose volume, open medical fluid
Pump send water to dilute preparing tank, opens dilute preparing tank stirring, after water for injection pump in dense preparing tank, closing concentrated compounding pipeline valve and
Concentrated compounding spray pump；
(3) dilute with preparation:
A, dilute preparing tank stirring is closed, water for injection inlet valve is opened, is put into dilute preparing tank through 0.1 μm of super polyether sulfone filter
90 DEG C or more of water for injection of core filtering is to preparing total volume；Water for injection inlet valve is closed, 1500ml will be used with measured
Water for injection soaks uniform medicinal carbon and is added in dilute preparing tank, opens dilute preparing tank stirring, opens filter pump, and medical fluid passes through 19
One group of stud filter that root, filter diameter are 3 μm；3, filter diameter be 0.1 μm of one group of polypropylene filter core；3, filter diameter be 0.1 μm
One group of super polyether sulfone filter core systemic circulation filter absorption, fluid temperature control at 70~90 DEG C；
B, after twenty minutes, sample detection pH value is adjusted stirring and adsorbing with through the filtered 2mol/L hydrochloric acid of 0.1 μm of filter membrane
PH value；
PH adjustment method: measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, linear addition under stiring
In dilute preparing tank, stir evenly；PH value is adjusted to 4.7~5.8；It inverse can only cannot adjust along adjusting when adjusting, after pH value meets regulation, take
Sample detection；
C, after medicinal liquid clarity, pH value, visible foreign matters, content detection are qualified, further next procedure operation；
D, it should must not exceed 3 hours to dilute with end since concentrated compounding.
The present invention relates to C grade, the B grades of unified standards using pharmacy corporation clean area in environment.
The present invention is on making control quality base to supplementary material, outside filtration system such as injection water, purified water, bottle
It washes, bottle fine purifiation, great circulation system, filling clean work area domain, and the preparation of stock, concentrated compounding, dilute preparation aspect of matching control as strict as possible
The nucleus quantity of product crystallization is influenced, control reduces tiny particulate matter and quantity；Control bottle essence in process of production
Detergent degree, process equipment bring into particle, personnel operation bring particle into, clean environment brings particle into, rubber plug cleaning particle, thus
It realizes that this product inherent quality is the quality product produced under a reliable quality guarantee system, reduces in selling period
Between appearance mannitol crystallization ratio, provide good product for clinical application, this series of technology combination
That the comprehensive of the invention embodies, devitrification problem of the present invention in finished product is resolved, also it is of the invention it is imaginary not
The technical effect arrived and creative technical contribution.
The technology of the present invention creativeness is mainly reflected in:
1. material preparation process is increased, operation under the B grade environmental condition that stock operation is under C grades of background, raw material mistake
No. nine sieves (200 mesh: 75 μm ± 4.1 μm), raw material powder or raw material become easily because physical external force squeezes agglomeration after sieving
The superfine powder of dissolution improves rate of dissolution.
2. 0.22 μm of filter core end-filtration of former water for injection has been eliminated, using 0.1 μm of super filter core end-filtration, practice
It proves, filter effect is better than original process.
3. specifying the preparation method and method of adjustment of pH adjusting agent: first measuring 180ml concentrated hydrochloric acid, inject water to
1000ml shakes up, and filters through 0.1 μm of filter membrane up to 2mol/L salt acid regulator；PH adjustment method: measurement needs additional amount
2mol/L hydrochloric acid under stiring in linear addition dilute preparing tank, stirs evenly in clean measuring cup；It can only be along tune when adjusting pH value
It inverse cannot adjust)
4. improving the use temperature of water for injection, it is 80 DEG C or more that original process, which require temperature, is determined by Experimental Comparison
90 DEG C -100 DEG C are more preferably preparing process.
5. increasing fine purifiation number, upgrade to 10 flushings by technological transformation by original 8 times, each washing pressure is not low
In 0.15Mpa.
Specific embodiment
The present invention by the following examples the present invention can be made into-step description, however, the scope of the present invention is simultaneously
It is not limited to following embodiments.
Embodiment 1:
The control of supplementary material packaging material quality:
(1) mannitol, injection stage；
(2) active carbon, pharmaceutical grade；
(3) water for injection, using polyether sulfone material, aperture be 0.1 μm of super filter element filtering, aperture is smaller, retention it is thin
Small particulate matter is more, and particulate matter plays the role of nucleus in crystallization process, final to reduce medical fluid in bottle not
Dissolubility particle and quantity control nucleus from source and are formed, and prevent from inducing crystallization；
(4) PH regulator (2mol/L hydrochloric acid), pharmaceutical grade；
(5) glass infusion bottle, pharmaceutical grade material is solid, thinnest part thickness (body thickness >=1.5mm, bottom of bottle thickness >=2.5mm),
Inner surface is smooth, no calculus, no concave-convex not flat surface；
(6) butyl rubber plug, 22.8 type of pharmaceutical grade；
(7) aluminium lid, 22.8 type of pharmaceutical grade；
Preparation process control:
(1) stock up: the quality of sweet dew raw polyol has a major impact crystallization.To ensure that material quality is without exception before feeding intake,
Increase raw material in procedure for preparation and crosses No. nine sieves (200 mesh: 75 μm ± 4.1 μm), raw material powder or raw material because physical external force squeezes
Agglomeration becomes diffluent superfine powder after sieving.
(2) prepared by concentrated compounding:
A, dense preparing tank water for injection valve is opened, the water for injection through 0.1 μm of super filter element filtering about 30 is injected into tank
Ten thousand ml, not less than 90 DEG C of water temperature (166 DEG C of mannitol fusing point, water temperature control is preferred at 90 DEG C -100 DEG C), close injection water valve
Door.It is 19 1 group that into tank, investment, which forms the medical charcoal 80g(stud filter of stud surface filtering layer, and filter diameter is 3 μm), it opens
Stirring is opened, spray pump is started, is recycled 25 minutes, medical charcoal is made uniformly to be gathered in stud outer surface, opens blowdown valve, discharge.Together
Method is dilute with forming filtering layer on the stud filter used；
B, the feeding cover for opening two dense preparing tanks respectively, into dense preparing tank, 90 DEG C of addition or more filters through 0.1 μm of polyether sulfone
800,000 ml of water for injection of core filtering, opens stirring, opens steam blowdown valve → steam valve, is heated to boiling；Amount of preparation will be weighed up
Mannitol be divided into two parts (every part of 480kg), respectively slowly investment two dense preparing tanks in, range estimation dissolution completely, be separately added into
720g active carbon rinses top tank structure well with 90 DEG C or more of water for injection, estimates noresidue, cover feeding cover, continue to stir
It mixes；
C, boiling 40 minutes, (it is related whether crystallization thoroughly sufficiently dissolves with bulk pharmaceutical chemicals in production process, and proper extension boils
Time, mannitol dissolubility are more thorough), steam off valve → steam blowdown valve stops stirring, concentrated compounding terminates；Concentrated wiring liquid is spare；
D, spray pump is opened, the mannitol concentrated solution by the good temperature of two tank concentrated compoundings not less than 85 DEG C is while hot through stud respectively
Filtering is sent into dilute preparing tank, after dense preparing tank medical fluid has been sent, successively with 90 DEG C or more of the note through 0.1 μm of polyether sulfone filter element filtering
It penetrates and is rinsed with water concentrated compounding top tank structure, estimate noresidue, open spray pump, water is sent to dilute preparing tank, continues to put into dense preparing tank
90 DEG C or more of water for injection (about the 1/3 of dose volume) through 0.1 μm of polyether sulfone filter element filtering opens spray pump and send water
To dilute preparing tank, dilute preparing tank stirring is opened, after water for injection has pumped in dense preparing tank, closes concentrated compounding pipeline valve and concentrated compounding medical fluid
Pump.
(3) dilute with preparation:
A, dilute preparing tank stirring is closed, water for injection inlet valve is opened, is put into dilute preparing tank through 0.1 μm of polyether sulfone filter core mistake
90 DEG C or more of water for injection of filter extremely prepares 4,800,000 ml of total volume.Water for injection inlet valve is closed, by load weighted 960g medicine
It is added in dilute preparing tank with active carbon (uniform with the wetting of 1500ml water for injection), opens dilute preparing tank stirring, open filter pump, medical fluid
By 1 group of stud filter (being 19 1 group, filter diameter is 3 μm), 1 group of polypropylene filter core (being 31 group, filter diameter is 0.1 μm), 1
Group polyether sulfone filter core (being 31 group, filter diameter is 0.1 μm) systemic circulation filtering absorption, fluid temperature are controlled at 70~90 DEG C；
B, after twenty minutes, sample detection pH value (first measures the dense salt of 180ml with 2mol/L salt acid for adjusting pH value to stirring and adsorbing
Acid injects water to 1000ml, shakes up, and filters through 0.1 μm of filter membrane up to 2mol/L salt acid regulator；PH adjustment method:
Measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, under stiring in linear addition dilute preparing tank, stirs evenly；It adjusts
Inverse can only cannot be adjusted along adjusting when pH value) to 4.7~5.8, after pH value meets regulation, notify QC personnel sample detection；
C, after medicinal liquid clarity, pH value, visible foreign matters, content detection are qualified, QA notifies next procedure operation；
D, it should must not exceed 3 hours to dilute with end since concentrated compounding.
Bottle washing procedure control:
A, outer bottle washing machine, ultrasonic bottle washing machine are successively opened, adjusting is slightly washed and the every group of flushing of fine purifiation ultrasonic type bottle washing machine
Water pressure is allowed to not less than 0.15MPa.It observes bottle and arranges flushing effect, adjust shower water and compare position of bottleneck；
B, glass bottle is put on outer bottle washing machine conveyer belt, rejecting obviously has breakage, oil bottle, calculus, coarse, interior has cobweb
Or crackle rejected product；
C, outer bottle washing machine conveyer belt is opened, so that the movement velocity of glass bottle is maintained at 160~200 bottles/minute, glass bottle is through washout
Enter ultrasonic bottle washing machine after bottle machine scrub outer wall, outer wash water is purified water, and each flushing water pressure cannot be less than
0.15Mpa；
D, the glass bottle after slightly washing enters clean area ultrasonic type bottle washing machine fine purifiation, and fine purifiation is divided into 10 flushings, it is contemplated that
Hot water injection's effect is better than cold water flushing effect, is first not less than 85 DEG C of waters for injection with the temperature through 0.1 μm of super filter element filtering
Recycle-water rinses 4 times, then rinses 4 times with through 0.1 μm of super filter element filtering purified water, most afterwards through 0.1 μm of super filter element filtering
Not less than 90 DEG C waters for injection of temperature rinse 2 times, and pressure of washing by water every time cannot be less than 0.15Mpa.Glass bottle 24 after taking cleaning
A, temperature of the injection through 0.1 μm of super filter element filtering is not less than 90 DEG C of waters for injection, after checking that visible foreign matters are qualified, formally opens
Beginning wash bottle, it is unqualified if any 1/24,120~160 bottle/minute of wash bottle speed need to be adjusted, increases flushing water and rinses the inner bottle wall time；
E, the glass bottle after fine purifiation rejects the rejected products such as damaged or breach, inputs bottling department by conveyer belt and uses.Wash bottle
Process should take 24, glass bottle after cleaning for every 2 hours, inject water for injection, check visible foreign matters.
Wash plug process control:
A, installation and connection purge tank, pipeline, pump, filter etc., wherein filter is provided with polyether sulfone filter core 2, hole
Diameter is 0.1 μm.
B, only by ∮ 22.8:18000-23000；Butyl rubber plug to be washed pours into plug washing machine, opens the injection on plug washing machine
With penstock, until water for injection fills plug washing machine, and in overflow to overflow tank.Water for injection temperature is controlled at 60~80 DEG C；
C, when water level is higher than 1/3 height in overflow tank, water for injection inlet valve on plug washing machine is closed, opens circulation
Pump keeps the pressure of pump after-filter to be not less than 0.10Mpa, rubber plug is made gently to roll in plug washing machine；
D, rinsing after ten minutes, closes circulating pump, opens blowdown valve and drains the ejected wash water in plug washing machine, closes blowdown valve；
E, it repeats above operation, after continuing rinsing 2 times, takes washing water to check visible foreign matters, stop cleaning after qualified；
F, it is transferred in clean capping stainless steel barrel, is enclosed by qualified butyl rubber plug has been cleaned using stainless steel strainer
The name of an article, lot number, quantity, cleaning people, the status indicator for cleaning date, scavenging period, it is spare；
G, rubber plug of the storage more than 4 hours can use after need to cleaning again after cleaning.
Filling process control:
A, after receiving mannitol preparation liquid detection return on qualification, closing is dilute with stirring, and opening is dilute to be assigned to filling medical fluid valve
Door starts spray pump, makes medical fluid by filtration system and reflux line circulation 10 minutes or more, medical fluid is through stud filter and cylinder
After the filtering of formula filter, send to filling process, fluid temperature maintains 65~70 DEG C；
B, from neck between plug is washed, to enter to have cleaned qualified butyl rubber plug spare to bottling department, confirms the status indicator of butyl rubber plug
Complete errorless, quantity and specification meet production requirement；
C, start smart bottle washing machine conveyer belt, start bottle placer host power supply, control conveying tape running speed is 160~200
Bottle/point.
D, filling area's environment temperature control is 50~60% in 20~25 DEG C, humidity, and background should purify item in the B grade under C grades
Operation under part, operation number are that few walk about to avoid excessive personnel causes to form nucleus in floating particle introducing infusion bottle as far as possible,
Crystallization is precipitated to induce formula mannitol injection liquid.Number, the size of particle directly affect the crystallization of mannitol in finished product, and particle contains
Amount is few, and particle is small to be not easy to form crystallization, and fraction of particle is more, and crystallization is precipitated in particle great Yi；
E, infusion bottle is rotated automatically into bottle placer, bottle placer, after confirmation bottle inlet, bottle placer movement are errorless, opens medical fluid
Valve makes medical fluid enter beginning in bottle placer filling；
F, bottle placer is adjusted, loading amount is made to stably keep 251-255ml, checks and is formally opened after loading amount, visible foreign matters are qualified
Begin filling；
G, the substandard products generated in pouring process are forbidden to recycle, and prevention released liquor potential risk that may be present causes
Possible pollution；
H, the qualified butyl rubber plug of rinsing is fitted into stopper-adding machine hopper, opens conveyer belt, open stopper-adding machine switch, observation
After stopper-adding machine works well, conveyer belt is opened by the glass bottle for having filled medical fluid and is sent into stopper-adding machine bottle inlet machine, the glass bottle of irrigation liquid passes through certainly
It moves after jumping a queue, then lid process is rolled by conveyer belt feeding.
I, loading amount, a visible foreign matters are checked in pouring process per hour.It must not exceed 4 with end to filling end from dilute
Hour.
Roll the control of lid process:
A, the aluminium-plastic cap that confirmation neck enters has the complete mark such as the name of an article, lot number, specification, quantity, supplier, checks material
Packaging should be without breakage；
B, start cover blanking machine, Cover-rolling machine, adjust capping mechanism, confirm it is each roll headkerchief roll lid satisfactory quality；
C, aluminium lid is poured into cover blanking machine oscillation bucket, starts conveyer belt, the Cover-rolling machine speed of service is adjusted, with filling speed
Match；
D, start to roll lid, lid quality should be rolled check at any time by rolling lid process, reject roll lid rejected product in time；
E, it rolls lid drug for every 24 bottles of 2 hours continuous drawings, must not there is aluminium lid loosening, crimping, rake angle, lid quality symbol is rolled in inspection
Close regulation.
Sterilization process control:
A, water, electricity, gas, the vapour of confirmation sterilizing cabinet auxiliary meet the requirements.
Steam pressure 0.3-0.5Mpa
Cooling water pressure 0.3-0.5Mpa
Compressed air pressure 0.5-0.8Mpa
Purify water pressure 0.15-0.3Mpa
If not reaching requirements above, forbid to be switched on；
B, the firstling of production should replace the reference bottle for placing probe；
C, the product after rolling lid is packed into vehicle of sterilization by sterilizing post employee by authenticated load mode, each vehicle of sterilization
After filling suspension indicate the name of an article, batch number, specification, state subject to sterilization Sign Board；
D, product subject to sterilization is pushed into sterilizing cabinet, closes sterilizing cabinet into cabinet door；
E, the name of an article (formula mannitol injection liquid), lot number, specification (250ml:50g), production date are set in intellective sterilization controller system
Phase, sterilising temp (115 DEG C), sterilization time (30 minutes), F0 value (8), the temperature that offers for sale (≤65 DEG C), operator, review people etc.
Information；
F, start sterilizing program, start to sterilize.
Shutdown → water filling → heating → sterilizing → cooling → draining → enabling → natural cooling → end
Water filling: purified water is injected into cabinet.
Heating: program is transferred to the temperature rise period after being delayed 0.5 minute after water level reaches.
Sterilizing: when temperature measuring point temperature reaches program setting temperature, program is transferred to sterilization phase.
Cooling: when the F0 value of temperature measuring point reaches programmed values, and sterilization time reaches programmed values, and program is transferred to
Cooling stage, the control of cooling procedure cooling water temperature should should be 30 minutes or so cooling time at 75-85 DEG C.
Draining: when temperature is down to cooling setpoint temperature, cooling procedure terminates, and program is transferred to the water stage in row's cabinet.
Emptying: after waiting drainings, interior room pressure drops to setting value, water pneumatic operated valve in the row's of closing cabinet.
Record: when sterilizing program terminates.Printing sterilizing tendency chart, records operation result.
G, offer for sale: sterilizing program terminates, and opens sterilizing cabinet and goes out cabinet door, removes sterilising prods, hang up and indicate the name of an article, product
Lot number, specification, quantity, sterilizing state Sign Board.It send to the product working area that sterilized, natural cooling after offeing for sale, without using again
The cooling of cooling water washing medicine bottle；
H, medical fluid terminates to the interval time sterilizing to must not exceed 2 hours since the filling lid that rolls.
The control of lamp inspection process:
A, bottle personnel take out sterilising prods under lamp inspection, on lower bottle machine push-in conveyer belt, open conveyer belt；
B, after lamp inspection product are sent into lamp inspection room, lamp inspection personnel do upper corresponding dedicated mark with respective colour code pen on aluminium-plastic cap
Note, after bubble collapse, portable bottleneck is visually inspected under black background by bottle in barn door edge；
C, lamp inspection personnel should hold bottleneck at away from 20~25cm of eye with thumb, index finger, middle finger, take it is upright, horizontal, fall
Vertical three-step approach rotation checks, makes visible foreign matters suspension (not make to generate bubble degree in bottle) that may be present, sight in medical fluid
It being checked from bottom to top, every bottle of review time is no less than 4 seconds, and repeatedly 1~2 time when necessary；
D, picked out when checking white point, white piece, color dot, color lump, vitroclastic, flake, fiber, muddiness, roll that lid sealing is tight, aluminium lid
The rejected products such as all or part falls off, pine lid, loading amount is insufficient, secondary bottle；
E, rejected product is counted and is recorded respectively by defect kind, and rejected product is put into turnover box, and is obviously marked
Know；
F, lamp inspection qualified product is put on outflow conveyer belt, is delivered to packaging post packaging；
G, the every work of lamp inspection personnel need to rest 20 minutes for 2 hours.
Packaging process control:
A, start label sticking machine, labeling product is sent into vanning position by conveyer belt, lot number, production on operator's inspection tag
The print quality on date, validity period rejects white bottle, tiltedly label, broken label product.
B, after the product removal label of rejecting, conveyer belt labeling again is returned.
C, the good drug of own labeling is fitted into carton, vanning personnel's confirmation is then placed in packing slip, qualification without neglected loading
Card/points for attention, covers backing plate, reaches cartoning sealing machine.
D, after product joint sealing by electronic supervision code, pay attention in two sides chest and spray head 2mm, camera is taken pictures clear height
Keep bright, rear electric eye keeps two blue lamps to light, and bar code should will be with chest in centre, preposition detent when taking pictures for camera
Equivalent width, system number are consistent with actual number, and fixed time cleaning spray head (dabs) by professional paper handkerchief, and cleaning camera lens is (clear with ear washing bulb
Manage camera lens), it is not allowed to be exclusively managed by a specially-assigned person from people before computer when without alarm.
E, it is packaged as required, pile is neat.
Correlation data:
The different crystallization formula mannitol injection liquid measurement results of table one
The formula mannitol injection liquid measurement result of two different pore size filter element filtering of table
The formula mannitol injection liquid measurement result (30 days) that table three is sieved, is not sieved
The sterilizing of table four is offerd for sale (80 DEG C) natural cooling, the formula mannitol injection liquid measurement result of washing cooling (30 days)
Five rubber plug of table is with water for injection rinsing times to formula mannitol injection liquid measurement result (14 days)
Six different temperatures water for injection of table is to formula mannitol injection liquid measurement result (14 days)
Claims (6)
1. a kind of process for producing for reducing formula mannitol injection liquid crystallization, supplementary material packaging material quality requirement is pharmaceutical grade and injection
Grade, by water for injection, purified water, bottle washout, bottle fine purifiation, preparation process, great circulation system, filling clean work area domain skill
Art combines to reduce formula mannitol injection liquid crystallization, including stock；Concentrated compounding preparation；It is dilute to match preparation；Wash bottle；Wash plug；It is filling；Roll lid；
Sterilizing；Lamp inspection；Packaging, which is characterized in that
Operation under the B grade environmental condition that stock operation is under C grades of background, raw material mannitol cross ± 4.1 μm of 200 mesh i.e. 75 μm
Sieve；Filtering uses 0.1 μm of super filter core end-filtration；The preparation method and method of adjustment of pH adjusting agent: it is dense first to measure 180ml
Hydrochloric acid injects water to 1000ml, shakes up, and filters through 0.1 μm of filter membrane up to 2mol/L salt acid regulator；PH value adjustment side
Method: measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, under stiring in linear addition dilute preparing tank, stirs evenly；
The use temperature of water for injection is determined as 90 DEG C -100 DEG C in mannitol process for preparation；Bottle fine purifiation number is 10 flushings, often
Secondary washing pressure is not less than 0.15Mpa.
2. a kind of process for producing for reducing formula mannitol injection liquid crystallization according to claim 1, which is characterized in that
(1) stock up: mannitol crosses 200 mesh in procedure for preparation: 75 μm of ± 4.1 μm of sieves become diffluent after sieving
Superfine powder；
(2) prepared by concentrated compounding:
A, dense preparing tank water for injection valve is opened, the water for injection through 0.1 μm of filter element filtering is injected into tank, water temperature is not less than
90 DEG C, close water for injection valve；Into tank, investment forms the medical charcoal of stud surface filtering layer, opens stirring, starts medical fluid
Pump recycles 25 minutes, and medical charcoal is made uniformly to be gathered in stud outer surface, opens blowdown valve, discharge；With same method, dilute
With forming filtering layer on the stud filter used；
B, the feeding cover for opening two dense preparing tanks respectively, be added into dense preparing tank 90 DEG C or more through 0.1 μm of polyether sulfone filter core mistake
The water for injection of filter opens stirring, opens steam blowdown valve and steam valve, is heated to boiling；The mannitol for weighing up amount of preparation is equal
It is divided into two parts, slowly after dissolution completely, active carbon is separately added into, with 90 DEG C or more of injection in two dense preparing tanks of investment respectively
It is rinsed with water clean top tank structure, noresidue covers feeding cover, continues to stir；
C, it boils 40 minutes, bulk pharmaceutical chemicals is allowed sufficiently to dissolve, steam off valve and steam blowdown valve stop stirring, concentrated compounding terminates；Concentrated compounding
Liquid is spare；
D, spray pump is opened, the mannitol concentrated solution by the good temperature of two tank concentrated compoundings not less than 85 DEG C is while hot through stud mistake respectively
Filter is sent into dilute preparing tank, after dense preparing tank medical fluid has been sent, successively with 90 DEG C or more of the injection through 0.1 μm of polyether sulfone filter element filtering
Concentrated compounding top tank structure is rinsed with water to noresidue, spray pump is opened, water is sent to dilute preparing tank, continues to be put into dense preparing tank through 0.1 μ
90 DEG C or more of water for injection of m polyether sulfone filter element filtering, the amount of being put into be dose volume 1/3, open spray pump by water send to
Dilute preparing tank opens dilute preparing tank stirring, after water for injection has pumped in dense preparing tank, closes concentrated compounding pipeline valve and concentrated compounding medical fluid
Pump；
(3) dilute with preparation:
A, dilute preparing tank stirring is closed, water for injection inlet valve is opened, is put into dilute preparing tank through 0.1 μm of polyether sulfone filter element filtering
90 DEG C or more of water for injection is to preparing total volume；Water for injection inlet valve is closed, 1500ml water for injection will be used with measured
It soaks uniform medicinal carbon to be added in dilute preparing tank, opens dilute preparing tank stirring, open filter pump, medical fluid is by 19, filter diameter
For 3 μm of one group of stud filter；3, filter diameter be 0.1 μm of one group of polypropylene filter core；3, one group that filter diameter is 0.1 μm
Absorption is filtered in the systemic circulation of polyether sulfone filter core, and fluid temperature is controlled at 70~90 DEG C；
B, stirring and adsorbing after twenty minutes, sample detection pH value, with through the filtered 2mol/L salt acid for adjusting pH value of 0.1 μm of filter membrane；
PH adjustment method: measurement needs the 2mol/L hydrochloric acid of additional amount in clean measuring cup, linear under stiring that dilute match is added
In tank, stir evenly；PH value is adjusted to 4.7~5.8；Can only be in the way of 2mol/L hydrochloric acid be added along adjusting when adjusting, it cannot be inverse
It adjusts, after pH value meets regulation, sample detection；
C, after medicinal liquid clarity, pH value, visible foreign matters, content detection are qualified, further next procedure operation；
D, it should must not exceed 3 hours to dilute with end since concentrated compounding.
3. a kind of process for producing for reducing formula mannitol injection liquid crystallization according to claim 2, which is characterized in that wash
Bottle process control:
A, outer bottle washing machine, ultrasonic bottle washing machine are successively opened, adjusting is slightly washed and every group of washing pressure of fine purifiation ultrasonic type bottle washing machine
Power is allowed to not less than 0.15MPa；
B, glass bottle is put on outer bottle washing machine conveyer belt, reject obviously have breakage, oil bottle, calculus, it is coarse, interior have cobweb or
The rejected product of crackle；
C, outer bottle washing machine conveyer belt is opened, so that the movement velocity of glass bottle is maintained at 160~200 bottles/minute, glass bottle is through outer bottle washing machine
Enter ultrasonic bottle washing machine after scrubbing outer wall, outer wash water is purified water, and each flushing water pressure cannot be less than 0.15Mpa；
D, the glass bottle after slightly washing enters clean area ultrasonic type bottle washing machine fine purifiation, and fine purifiation is divided into 10 flushings, first with through 0.1 μm
Not less than 85 DEG C water for injection recycle-waters of the temperature of filter element filtering rinse 4 times, then rinse 4 with through 0.1 μm of filter element filtering purified water
Secondary, not less than 90 DEG C waters for injection of temperature most afterwards through 0.1 μm of filter element filtering rinse 2 times, and pressure of washing by water every time cannot be less than
0.15Mpa；24, glass bottle after taking cleaning, temperature of the injection through 0.1 μm of filter element filtering is not less than 90 DEG C of waters for injection, and inspection can
After seeing that foreign matter is qualified, formally start wash bottle, it is unqualified if any 1/24,120~160 bottle/minute of wash bottle speed need to be adjusted, punching is increased
Wash water rinses the inner bottle wall time；
E, the glass bottle after fine purifiation rejects damaged or breach rejected product, inputs bottling department by conveyer belt and uses；Wash bottle process is answered
24, glass bottle after taking within every 2 hours cleaning, water for injection is injected, checks visible foreign matters.
4. a kind of process for producing for reducing formula mannitol injection liquid crystallization according to claim 3, which is characterized in that
Wash plug process control:
A, washing plug equipment includes purge tank, pipeline, pump and filter, and wherein filter is provided with polyether sulfone filter core 2, and aperture is
0.1μm；
B, butyl rubber plug to be washed is poured into plug washing machine, opens the water for injection valve on plug washing machine, until water for injection is infused
Full plug washing machine, and in overflow to overflow tank；Water for injection temperature is controlled at 60~80 DEG C；
C, when water level is higher than 1/3 height in overflow tank, water for injection inlet valve on plug washing machine is closed, opens circulating pump, is protected
The pressure of pump after-filter is held not less than 0.10Mpa, rubber plug is made gently to roll in plug washing machine；
D, rinsing after ten minutes, closes circulating pump, opens blowdown valve and drains the ejected wash water in plug washing machine, closes blowdown valve；
E, it repeats above operation, after continuing rinsing 2 times, takes washing water to check visible foreign matters, stop cleaning after qualified；
F, it is transferred in clean capping stainless steel barrel using stainless steel strainer by qualified butyl rubber plug has been cleaned, encloses product
Name, lot number, quantity, cleaning people, the status indicator for cleaning date, scavenging period, it is spare；
G, rubber plug of the storage more than 4 hours can use after need to cleaning again after cleaning.
5. a kind of process for producing for reducing formula mannitol injection liquid crystallization according to claim 4, which is characterized in that fill
Fill process control:
A, opening is dilute is assigned to filling medical fluid valve, starts spray pump, medical fluid is made to pass through filtration system and reflux line circulation 10
Minute or more, medical fluid is sent to filling process, fluid temperature maintains 65~70 after stud filter and filter cartridge filtering
℃；
B, confirm that the status indicator of butyl rubber plug is completely errorless, quantity and specification meet production requirement；
C, start smart bottle washing machine conveyer belt, start bottle placer host power supply, control conveying tape running speed；
D, filling area's environment temperature control is 50~60% in 20~25 DEG C, humidity, and background should be under the B grade purification condition under C grades
Operation, while avoiding that floating particle is artificially caused to introduce formation nucleus in infusion bottle；
E, infusion bottle is rotated automatically into bottle placer, bottle placer, after confirmation bottle inlet, bottle placer movement are errorless, are opened medical fluid valve, is made
It is filling that medical fluid enters beginning in bottle placer；
F, bottle placer is adjusted, loading amount is stablized, is formally started after inspection loading amount, visible foreign matters are qualified filling；
G, the substandard products generated in pouring process are forbidden to recycle；
H, the qualified butyl rubber plug of rinsing is fitted into stopper-adding machine hopper, opens conveyer belt, open stopper-adding machine switch, observation is jumped a queue
After machine works well, conveyer belt is opened by the glass bottle for having filled medical fluid and is sent into stopper-adding machine bottle inlet machine, the glass bottle of irrigation liquid adds through automatic
After plug, then it is sent by conveyer belt and rolls lid process；
I, loading amount, a visible foreign matters are checked in pouring process per hour；With terminating, to filling end, to must not exceed 4 small from dilute
When.
6. a kind of process for producing for reducing formula mannitol injection liquid crystallization according to claim 5, which is characterized in that go out
The control of bacterium process:
A, water, electricity, gas, the vapour of confirmation sterilizing cabinet auxiliary meet the requirements:
Steam pressure 0.3-0.5Mpa
Cooling water pressure 0.3-0.5Mpa
Compressed air pressure 0.5-0.8Mpa
Purify water pressure 0.15-0.3Mpa
If not reaching requirements above, forbid to be switched on；
B, the firstling of production should replace the reference bottle for placing probe；
C, the product after rolling lid is packed into vehicle of sterilization by sterilizing post employee by authenticated load mode, and each vehicle of sterilization is filled
Afterwards suspension indicate the name of an article, batch number, specification, state subject to sterilization Sign Board；
D, product subject to sterilization is pushed into sterilizing cabinet, closes sterilizing cabinet into cabinet door；
E, setting includes the name of an article, lot number, specification, date of manufacture, 115 DEG C of sterilising temp, sterilization time in intellective sterilization controller system
30 minutes, F0 value 8, temperature≤65 DEG C of offeing for sale, operator and review people's information；
F, start sterilizing program, start to sterilize；When sterilizing terminates, printing sterilizing tendency chart records operation result；
G, offer for sale: sterilizing terminates, and opens sterilizing cabinet and goes out cabinet door, removes sterilising prods, hang up and indicate the name of an article, batch number, rule
Lattice, quantity, sterilizing state Sign Board；It send to the product working area that sterilized, natural cooling after offeing for sale, without being rushed again with cooling water
The cooling of wash bottle；
H, medical fluid terminates to the interval time sterilizing to must not exceed 2 hours since the filling lid that rolls.
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| CN106963779A (en) * | 2017-04-20 | 2017-07-21 | 南京正科医药股份有限公司 | A kind of production method of compound potassium dihydrogn phosphate |
| CN108324684A (en) * | 2018-01-26 | 2018-07-27 | 湖北康沁药业股份有限公司 | A kind of preparation method of formula mannitol injection liquid |
| CN115887365B (en) * | 2022-11-19 | 2023-07-25 | 华夏生生药业(北京)有限公司 | Mannitol injection and its production process |
| CN116983258B (en) * | 2023-07-25 | 2024-03-22 | 河南双鹤华利药业有限公司 | Preparation process of mannitol injection not easy to crystallize |
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| JPH04368347A (en) * | 1991-06-18 | 1992-12-21 | Towa Kasei Kogyo Kk | Production of mannitol and mannose |
| CN103432066A (en) * | 2013-07-23 | 2013-12-11 | 蚌埠丰原涂山制药有限公司 | Compound mannitol injection and preparation method thereof |
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